Ophthalmic Products Notes

Anatomy of the Eye

  • Cornea
  • Iris
  • Conjunctiva
  • Sulcus circularis corneae
  • Posterior chamber
  • Lens
  • Rectus lateralis
  • Vitreous Body
  • Nerve sheath
  • Ciliary body
  • Zonular spaces
  • Hyaloid canal
  • Rectus medialis
  • Sclera
  • Choroid
  • Retina
  • Fovea centralis
  • Optic nerve
  • A. centralis retinae

Types of Ophthalmic Products

  • Eye Drops: Aqueous or oily solutions or suspensions for instillation in the eye cavity.
  • Eye Ointments: Semisolid preparations with oleaginous or water-soluble bases.
  • Eye Packs: Materials soaked with solutions for insertion into the superior or inferior fornix.
  • Eye Discs: Gel matrices for slow drug release.
  • Eye Lotions: Solutions kept in contact with the cornea in an eye cup.
  • Intraocular Solutions: Used during eye surgery; must be preservative-free and buffer-free.

Pros of Ophthalmic Products

  • Direct application to the site of action.
  • Local application ensures minimal side effects.
  • Allows for self-application.

Cons of Ophthalmic Products

  • Poor drug retention at the site of action.
  • Requires frequent administration, which can be inconvenient and lead to non-compliance.
  • Formulations must be sterile, requiring specialized manufacturing facilities.
  • Ointment application may cause temporary blurred vision.
  • Pain and irritation are major side effects.

Desirable Qualities of Ophthalmics

  • Sterility: Absence of microorganisms, especially Pseudomonas aeruginosa. Staphylococcus is a common contaminant.
  • Freedom from Foreign Particles
  • Appropriate Tonicity
  • pH: Optimal comfort at pH 7.4, but pH 6-8 is generally acceptable. pH affects therapeutic activity, solubility, and stability.
  • Surface Activity: Ability to wet tissues.
  • Clarity: Achieved with sintered glass filter or hard-surfaced Whatman F/paper #54.
  • Appropriate Viscosity
  • Good Corneal Penetration
  • Prolonged Contact Time with corneal tissue.
  • Simplicity of Instillation for the patient.
  • Non-Irritative and Comfortable

Categories of Aqueous Ophthalmic Dosage Forms

  • Solutions: Majority are formulated as solutions.
  • Suspensions:
    • Formulated as suspensions when the medicament has stability issues.
    • Potency of lipid-soluble drug is greater than that of water-soluble salts.
    • 95% of dispersed particles should have an average particle diameter less than 10 micrometers.

Formulation of Ophthalmic Drops

  • Active Pharmaceutical Ingredient
  • Vehicle: Aqueous or oily
  • Preservative
  • Adjuvants: To adjust tonicity, viscosity, or pH
  • Suitable Container

Vehicle

  • Aqueous and Non-aqueous vehicles
  • Predominantly used vehicle is Purified Water
  • Occasionally oil is used if the therapeutic agent is unstable within an aqueous vehicle

Preservation of Ophthalmics

  • Multiple-dose containers require preservatives to prevent growth or destroy microorganisms introduced during use.
  • If contamination occur, other doses may cause infection to eye

Preservatives

  • Required for multidose formulations.
  • Types:
    • Cationic preservatives
    • Esters of parahydroxybenzoates (parabens)
    • Organic alcohols
    • Organic mercurial compounds

Cationic Preservatives

  • Examples: Benzalkonium chloride and benzethonium chloride.
  • Incompatible with anionic therapeutic agents like pilocarpine nitrate and physostigmine, and substances used in diagnosis of ocular conditions like sodium fluorescein.
  • May be incompatible with non-ionic hydrophilic polymers used to modify viscosity.

Cationic Preservatives - Benzalkonium Chloride

  • Used in concentrations between 0.002 and 0.02% w/v (typically 0.01% w/v).
  • 0.1% w/v disodium edetate can be used to enhance microbial activity.
  • Antimicrobial properties decrease when the pH falls below 5.

Cationic Preservatives - Benzethonium Chloride

  • Commonly used in concentrations within the range of 0.01–0.02% w/v.
  • Exhibits lower antimicrobial activity than benzalkonium chloride.

Esters of Parahydroxybenzoates (Parabens)

  • Mixtures of methyl and propyl esters of parahydroxybenzoic acid.
  • Used in combined concentrations typically at 0.2% w/w.
  • May contribute to ocular irritancy, limiting their use.

Organic Alcohols

  • Two main organic alcohols used as preservatives:
    • Chlorobutanol
    • Phenylethylalcohol

Chlorobutanol

  • Typically used at a concentration of 0.5% w/v.
  • Reserved for acidic ophthalmic preparations.
  • Volatile and can be lost from solution if stored in polyolefin containers due to partitioning.
  • Formulations with chlorobutanol must be stored in glass containers.
  • Has solubility issues and may precipitate below room temperature.

Phenylethylalcohol

  • Typical concentration used is 0.25–0.50% v/v.
  • Poor solubility, volatile, and may partition into plastic containers.

Organic Mercurial Compounds

  • Antimicrobial agents containing mercury.
  • Not commonly used due to environmental and toxicity concerns.
  • Examples:
    • Phenylmercuric acetate: 0.001–0.002% w/v
    • Phenylmercuric nitrate: 0.002% w/v
    • Thimerosal: 0.001–0.15% w/v (solutions) and 0.001–0.004% w/v (suspensions)

Viscosity-Modifying Agents

  • Hydrophilic polymers added to ophthalmic solutions to:
    • Control the rate at which the drop flows out of the container.
    • Control the residence time of the solution within the precorneal environment.
  • A critical formulation viscosity threshold exists (circa 55 mPa/s), above which there is no further increase in contact time between the dosage form and the eye.

Ideal Properties of Viscosity-Modifying Agents

  • Easily filtered
  • Easily sterilized
  • Compatible with other components
  • Examples: Hydroxypropylmethylcellulose, Poly(vinyl alcohol)
  • Poly(acrylic acid) is commonly used for the treatment of dry-eye syndrome and may increase the viscosity of formulations containing a therapeutic agent.

pH Adjusting Agents

  • Ideally, the pH of ophthalmic solutions should be controlled at 7.4 (pH of tear fluid).
  • Choice of formulation pH is dictated by the stability of the therapeutic agent, absorption of the active agent across the cornea, and patient comfort.

pH Adjusting Agents - Considerations

  • Tears have natural buffering capacity.
  • Some drugs are quite acidic and can overtax the buffering capacity of lacrimal fluid.
  • Some drugs are insoluble in water at pH 7.4.
  • The pH at which a drug has the greatest activity may also be the pH at which the drug is most unstable.
  • A compromise must be reached and that pH maintained using buffers.
  • Buffers prevent pH changes, such as leaching of alkali from glass containers.

Buffering Agents

  • Borate buffer (boric acid/borax): pH range 6.8 to 9.1
  • Phosphate buffer (sodium acid phosphate/sodium phosphate): pH range 4.5 to 8.5
  • Citrate buffer (citric acid/sodium citrate): pH range 2.5 to 6.5

Tonicity Adjusting Agents

  • Each ingredient in the formulation contributes to tonicity.
  • The sodium chloride equivalent is the amount of sodium chloride that will give the same tonic effect as 1 g of the drug.
  • For example, the NaCl equivalent of pilocarpine HCl is 0.24, meaning 1 g of pilocarpine will have the same tonic effect as 0.24 g of NaCl.

Tonicity Adjusting Agents - Considerations

  • Lacrimal fluid is isotonic with blood, having an isotonicity value corresponding to that of a 0.9% NaCl solution.
  • Commonly used isotonicity adjusting ingredients include NaCl, KCl, dextrose, glycerin, propylene glycol, and mannitol.

Antioxidants

  • Used for therapeutic agents that degrade by oxidation.
  • Sodium sulfite:
    • Used at a concentration of 0.1% w/v.
    • Preferred at alkaline pH.
    • Must be protected from light.

Antioxidants - Sodium Metabisulphite

  • Used at a concentration of 0.1% w/v.
  • Preferred at acid pH.
  • Must be protected from light.
  • Marked antimicrobial properties at acid pH.
  • Enhances the activity of phenylmercuric nitrate at acid pH.
  • Has incompatibility problems.

Chelating Agents

  • Example: Disodium edetate.
  • Chelates metal ions and improves stability.
  • Prevents oxidation of certain drugs.
  • 0.1% concentration enhances antibacterial activity and chemical stability.

Formulation of Eye Lotions

  • Sterile
  • No preservative
  • Isotonic with lacrimal fluids
  • Neutral pH
  • Large volume
  • Non-irritant to ocular tissue

Preparation of Ophthalmic Solutions and Suspensions

  • A single drop of ophthalmic solution or suspension measures 50 µL based on 20 drops/mL.
  • Optimal volume based on eye capacity is 5-10 µL.

Preparation of Ophthalmic Solutions

  • Preparation of the solution
  • Clarification: Pore size 0.45 - 1.2 mcm
  • Filling and sterilization:
    • Autoclaving: 115 °C, 30 mins or 121 °C, 15 mins
    • Heating at 98-100 °C for 30 minutes with preservative.
    • Filtration through membrane filter: 0.22mcm pore size.
    • Dry Heat at 160 °C for 2 hrs. for non-aqueous

Methods of Sterilization

  • Sterile membrane filtration under aseptic conditions.
    • Not suitable for suspensions.
  • Sterilization by autoclaving in the final container.
    • Not suitable for heat-labile drugs & plastic containers.
  • Gas, as ethylene oxide, or Ionizing Radiations, as gamma rays
    • But

Preparation of Ophthalmic Suspensions

  • Solution used to prepare suspension is clarified first.
  • Solid to be dispersed is first sterilized by heat, ethylene oxide gas, or gamma radiation.
  • Particle size must be micronized (finely subdivided).
  • Suspended particles must not associate to larger ones on storage.
  • Suspension must be gently shaken before use.

Ophthalmic Ointments

  • Interfere with vision unless used at bedtime only.
  • Ointments, suspensions, and gels mix well with lacrimal fluid, enhancing retention and activity.
  • Dispensed in small sterilized tubes made of plastic or metal.
  • Tubes should contain not more than 5 g of preparation and be fitted with a nozzle to facilitate administration.
  • Must be free from particulate matter.

Preparation of Ophthalmic Ointments

  • Ointments must be sterile.
  • Typically manufactured and packaged under aseptic conditions.
  • Components of the base are prepared in an enclosed mixing vat to which heat may be applied to aid dissolution and mixing of the ingredients and, importantly, to sterilize the ointment base.
  • Sterile active ingredient is then added and mixed until homogenous.

Ophthalmic Ointment Bases

  • Hydrocarbon bases:
    • Mixture of paraffins (white or yellow).
    • High incidence of blurred vision.
  • Non-emulsified absorption bases:
    • Composed of one or more paraffins (e.g., liquid and yellow soft paraffin) and a sterol-containing emulsifying agent (e.g., lanolin derivatives).
    • Less greasy, allows incorporation of aqueous drug.

Ophthalmic Ointment Bases Cont’d

  • Water-soluble bases/aqueous gels:
    • Lower incidence of blurred vision.
    • Water-soluble bases usually formulated using polyethylene glycols.
    • Aqueous gels composed of poly(acrylic acid) are devoid of therapeutic agents and are often used for the treatment of keratoconjunctivitis sicca (dry-eye syndrome).

Packaging for Ophthalmic Products

  • Regarded as part of the formulation.
  • Should protect from microbial contamination, moisture, and air.
  • Material should not leach into the product, nor absorb/adsorb the product.
  • If terminally sterilized, should withstand the process.
  • May be glass or plastic - up to 10 ml

Packaging for Ophthalmic Products - Plastic

  • Packaged primarily in plastic dropper bottles (the Drop-Tainer® plastic dispenser).
  • Advantages of the Drop-Tainer:
    • Convenience of use by the patient
    • Decreased contamination potential
    • Lower weight
    • Lower cost
  • Plastic bottle and dispensing tip are made of low-density polyethylene (LDPE) resin, which provides the necessary flexibility and inertness.
  • The cap is made of harder resin than the bottle.

Packaging for Ophthalmic Products - Plastics - LDPE Resin

  • Advantage of LDPE resin:
    • Compatible with a very wide range of drugs and formulation components
  • Disadvantage of LDPE resin:
    • Sorption and permeability of components of the dosage form (e.g., volatile preservatives such as chlorobutanol)
    • Weight loss by water vapor transmission
    • Usually translucent, hence provides no protection for light-sensitive drugs; additional package protection is required (using an opacifying agent such as titanium dioxide)
  • LDPE resin can be sterilized by gamma irradiation or ethylene oxide

Packaging for Ophthalmic Products - Glass

  • The glass bottle is less commonly used.
  • Sterilized by dry-heat or steam autoclave sterilization.
  • Amber glass is used for light-resistance, hence offers more protection than plastic dropper bottles.
  • Has less sorption and permeation characteristics when compared to plastics.